The long term gal of this project is to advance our understanding of the genetic controls that guide cardiac development. Identifying and characterizing the transcription factors cascade that control cardiac development is an important step in understanding the genesis of congenital heart defects and important clinical disorders such as cardiac hypertrophy and heart failure.
The specific aim of this proposal is to identify the role of the jumonji gene (jmj) in the developing cardiovascular system. Neither the role of jmj in the cardiovascular development nor the molecular function of the jmj protein (JMJ) has been characterized. We generated the mutant mice that carry a homozygous mutation in jmj. Our analyses on jmj mutant mice revealed that jmj mutant embryos showed cardiac malformations including ventricular septal defect, double outlet right ventricle and non- compaction of the ventricular wall (thin ventricular wall), recapitulating human congenital heart disease. All mutants died soon after birth. Therefore, the underlying mechanisms of these cardiac defects will be examined in this proposal. JMJ is a novel protein whose molecular function remains unknown. JMJ contains the putative DNA binding domain that is homologous to the DNA binding transcription factor family, ARID. JMJ also contains the homologous region to the retinoblastoma binding protein (RBP) that binds to the retinoblastoma gene product (Rb). Rb is a key regulator of cell growth and differentiation. Our preliminary studies that JMJ is a DNA-binding nuclear protein that contains a transcriptional repressor domain. JMJ mediates cell growth and interacts with Rb. Based on these observations. my hypothesis is that JMJ is a DNA-binding transcription factor and regulate the myocardial cell growth by interacting with cofactors such as Rb. Therefore, the DNA-binding consensus motif of JMJ will be determined and its transcriptional function will be examined by a reporter gene assay. Molecular mechanisms by which JMJ mediates cell growth will be examined using cell lines and primary cultures from the wild type and jmj mutants. JMJ is a novel protein whose molecular function remains unknown. JMJ contains the putative DNA binding domain that is homologous to the DNA binding transcription factor family, ARID. JMJ also contains the homologous region to the retinoblastoma binding protein (RBP) that binds to the retinoblastoma gene product (Rb). Rb is a key regulator of cell growth and differentiation. Our preliminary studies indicate that JMJ is a DNA-binding nuclear protein that contains a transcriptional repressor domain. JMJ mediates cell growth and interacts with Rb. Based on these observations, my hypothesis is that JMJ is a DNA- binding transcription factor and regulate the myocardial cell growth by interacting with cofactors such as Rb. Therefore, the DNA-binding consensus motif of JMJ will be determined and its transcriptional function will be examined by a reporter gene assay. Molecular mechanisms by which JMJ mediates cell growth will be examined using cell lines and primary cultur4es from the wild type and jmj mutants. JMJ may play a role in molecular events leading to cardiac hypertrophy and failure, since jmj continues to be expressed in the adult heart. Therefore, the outcome of this research will lead us to develop new therapies for both congenital and adult heart diseases.
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